Rationale: Renal fibrosis is the terminal manifestation of chronic and irreversible renal disease. Effective therapies other than dialysis are extremely limited. In this study, we investigated the potential effects of targeting elevated interleukin-6 (IL-6) levels in the treatment of renal fibrosis. Methods: Fc-gp130 was used to specifically block IL-6 trans-signaling. Unilateral ureteral occlusion (UUO) and ischemia reperfusion (IR) mouse models were constructed to investigate the therapeutic effect of Fc-gp130 on renal fibrosis. The role of IL-6 trans-signaling and phosphorylation of signal transducer and activator of transcription (STAT) 3 in regulating fibroblast accumulation and extracellular matrix protein deposition were evaluated in cell experiments and mouse models. Results: The kidneys of mice with UUO were found to have elevated soluble IL-6 receptor (sIL-6R) levels in the progression of fibrosis. Fc-gp130 attenuated renal fibrosis in mice, as evidenced by reductions in tubular atrophy and the production of extracellular matrix protein. Blockade of IL-6 trans-signaling with Fc-gp130 also reduced inflammation levels, immune cell infiltration, and profibrotic cytokines expression in renal tissue, with decreased STAT3 phosphorylation and reduced fibroblast accumulation in the renal tissue. In vitro, Fc-gp130 also reduced the phosphorylation of STAT3 induced by transforming growth factor (TGF)-β1 in fibroblasts. Furthermore, the therapeutic effect of Fc-gp130 was confirmed in a model of acute kidney injury-chronic kidney disease. Conclusion: Overall, IL-6 trans-signaling may contribute to crucial events in the development of renal fibrosis, and the targeting of IL-6 trans-signaling by Fc-gp130 may provide a novel therapeutic strategy for the treatment of renal fibrosis.

中文翻译：

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阻断白细胞介素6反式信号转导可通过抑制STAT3激活来防止肾脏纤维化。

理由：肾纤维化是慢性和不可逆的肾脏疾病的最终表现。除透析以外的有效疗法极为有限。在这项研究中，我们调查了靶向升高的白介素6（IL-6）水平在治疗肾纤维化中的潜在作用。方法：使用Fc-gp130特异性阻断IL-6反式信号转导。构建了单侧输尿管闭塞（UUO）和缺血再灌注（IR）小鼠模型，以研究Fc-gp130对肾纤维化的治疗作用。在细胞实验和小鼠模型中评估了IL-6的信号转导和转录激活子（STAT）3的信号转导和磷酸化在调节成纤维细胞积累和细胞外基质蛋白沉积中的作用。结果：发现UUO小鼠的肾脏在纤维化进程中具有较高的可溶性IL-6受体（sIL-6R）水平。Fc-gp130可减轻小鼠肾纤维化，如肾小管萎缩的减少和细胞外基质蛋白的产生所证明。用Fc-gp130阻断IL-6反信号也可降低肾脏组织中的炎症水平，免疫细胞浸润和纤维化细胞因子表达，同时STAT3磷酸化降低和肾组织中成纤维细胞积累减少。在体外，Fc-gp130还减少了成纤维细胞中转化生长因子（TGF）-β1诱导的STAT3磷酸化。此外，在急性肾损伤-慢性肾脏疾病模型中证实了Fc-gp130的治疗作用。结论：总体而言，